Sirtuin 1 (SIRT1), originally identified as a longevity gene, is induced by caloric restriction, and regulates various cellular functions including DNA repair, cell survival and metabolism via the deacetylation of target proteins such as histone and p53. These functions are considered to act dualistically as preventing or facilitating cancer. This study aimed to clarify the expression and role of SIRT1 in endometrial carcinoma. Because a high-calorie diet was a well-known risk factor for endometrial carcinoma, we first hypothesized that SIRT1 might be downregulated in normal endometrial glandular cells of obese women. However, no correlation was observed between the expression of SIRT1 and body mass index (BMI). In contrast, regardless of BMI, the immunohistochemical expression of SIRT1 was significantly higher in endometrial carcinoma (108 cases) than in normal endometria (60 cases) (Po0.05), and its overexpression was associated with a shorter survival (Po0.05). Our experiments in vivo revealed that SIRT1 accelerated the proliferation of endometrial carcinoma cell lines (HHUA, HEC151, and HEC1B). SIRT1 overexpression significantly enhanced the resistance for cisplatin and paclitaxel in HHUA cells. Although p53 is an important target protein for SIRT1, the selective SIRT1 inhibitor (EX527) significantly suppressed the proliferation and cisplatin resistance of three endometrial carcinoma cell lines regardless of the p53 mutation status. In addition, SIRT1 overexpression in HHUA cells accelerated tumor growth and cisplatin resistance in nude mice, and EX527 significantly suppressed the growth of tumors of HHUA and HEC1B cells. No adverse effect of EX527 was observed in these mice. In conclusion, SIRT1 is involved in the acquisition of the aggressive behavior associated with endometrial carcinoma, and the SIRT1 inhibitor, EX527, may be a useful agent for the treatment of this malignancy.

BACKGROUND: SIRT1 is a longevity gene that forestalls aging and age-related diseases including cancer, and has recently attracted widespread attention due to its overexpression in some cancers. We previously identified the overexpression of SIRT1 in ovarian carcinoma (OvCa) as a poor prognostic factor. However, mechanistic insights into the function of SIRT1 in OvCa have yet to be elucidated. METHODS: Quantitative real-time reverse PCR (qRT-PCR) and Western blotting were employed to examine the expression of SIRT1 in a panel of human OvCa cell lines. si-RNA or sh-RNA and cDNA technologies were utilized to knockdown or overexpress SIRT1, respectively. The effects of SIRT1 on proliferation and chemoresistance were examined using a WST-1 assay, and the underlying mechanisms were confirmed using an apoptotic assay, and the quantification of glutathione (GSH), and reactive oxygen species (ROS). The aggressiveness of SIRT1 was analyzed using in vitro invasion and migration assays. RESULTS: SIRT1 was more strongly expressed in OvCa cell lines than in the immortalized ovarian epithelium at the gene and protein levels. Stress up-regulated the expression of SIRT1 in dose- and time-dependent manners. SIRT1 significantly enhanced the proliferation (P < .05), chemoresistance (P < .05), and aggressiveness of OvCa cells by up-regulating multiple antioxidant pathways to inhibit oxidative stress. Further study into the overexpression of SIRT1 demonstrated the up-regulation of several stemness-associated genes and enrichment of CD44v9 via an as-yet-unidentified pathway. CONCLUSIONS: Our results suggest that SIRT1 plays a role in the acquisition of aggressiveness and chemoresistance by OvCa, and has potential as a therapeutic target for OvCa.

PurposeLipocalin 2 (LCN2) is a secretory protein that is involved in various physiological processes including iron transport. We previously identified LCN2 as an up-regulated gene in endometrial carcinoma, and found that the overexpression of LCN2 and its receptor, SLC22A17, was associated with a poor prognosis. However, the functions and mechanism of action of LCN2 currently remain unclear.MethodsThe LCN2-overexpressing endometrial carcinoma cell lines, HHUA and RL95-2, and LCN2-low-expressing one, HEC1B, were used. The effects of LCN2 on cell migration, cell viability, and apoptosis under various stresses, including ultraviolet (UV) irradiation and cisplatin treatment, were examined using the scratch wound healing assay, WST-1 assay, and Apostrand assay, respectively.ResultsLCN2-silencing using shRNA method significantly reduced the migration ability of cells (p<0.05). Cytotoxic stresses significantly decreased the viability of LCN2-silenced cells more than that of control cells. In contrast, LCN2 overexpression was significantly increased cisplatin resistance. These effects were canceled by the addition of the iron chelator, deferoxamine. After UV irradiation, the expression of phosphorylated Akt (pAkt) was decreased in LCN2-silenced cells, and the PI3K inhibitor canceled the difference induced in UV sensitivity by LCN2. The cisplatin-induced expression of pAkt was not affected by LCN2; however, the expression of p53 and p21 was increased by LCN2-silencing.ConclusionsThese results indicated that LCN2 was involved in the migration and survival of endometrial carcinoma cells under various stresses in an iron-dependent manner. The survival function of LCN2 may be exerted through the PI3K pathway and suppression of the p53-p21 pathway. These functions of LCN2 may increase the malignant potential of endometrial carcinoma cells.

Sirtuin 1 (SIRT1), originally identified as a longevity gene, regulates DNA repair and metabolism by deacetylating target proteins such as p53. SIRT1 plays a key role in the pathophysiology of metabolic diseases and neurodegenerative disorders, and is considered to protect against age-related diseases including cancer. In contrast, SIRT1 may be oncogenic because its overexpression has been detected in many cancers. The aim of the present study was to clarify the expression and the role of SIRT1 in ovarian carcinoma (OvCa). The expression of SIRT1 was evaluated immunohistochemically in 16 cases of normal ovaries, 35 cases of endometriosis with/without carcinoma, and 68 cases of OvCa (endometrioid, 16; clear cell, 20; mucinous, 16; serous, 16). Staining results were evaluated semiquantitatively by the Immunoreactive Scoring System, and the relationships with clinicopathologic features and outcomes of patients were analyzed. The expression of SIRT1 was higher in endometrioid, mucinous, and clear-cell carcinomas than in the inclusion cysts of normal ovaries, but not in serous carcinoma (P=0.038). The expression of SIRT1 on OvCa did not correlate with age, stage, location of metastasis, or capsular penetration. However, elevated SIRT1 expression was a significant predictor of shorter survival in univariate (P=0.038) and multivariate (P=0.037) survival analyses, regardless of the tumor stage. Results of the present study suggest a positive role for SIRT1 in the development of OvCa and its potential as a novel therapeutic target.

Background. Pregnancy luteomas are rare, benign, ovarian neoplasms resulting from increased androgenic activity during pregnancy. Often, they occur asymptomatically and are only diagnosed incidentally during imaging or surgery: cesarean section or postpartum tubal ligation. Most common symptoms associated with pregnancy luteoma include acne, deepening of voice, hirsutism, and clitoromegaly. Most pregnancy luteomas regress spontaneously postpartum. Thus, the management of pregnancy luteomas depends on the clinical situation. Case. We report a case of 28-year-old gravida 2, para 1 who presented at 39 + 1 weeks of gestation with prolonged labor and delivered by emergency cesarean. Intraoperatively, a huge left ovarian mass was identified and resected, and tissue was sent for histopathology and a diagnosis of pregnancy luteoma was made after the pathological report. Conclusion. The present report emphasizes that pregnancy luteoma is a benign neoplasm and imprudent surgical intervention should be reserved. Proper imaging techniques, preferably MRI or ultrasonography that visualize the size of the ovary and reproductive hormonal profiles, would suffice for the diagnosis and management of pregnancy luteoma.

Objective Effective cancer treatment involves aggressive chemo-radiotherapy protocols that alter survivors’ quality of life (QOL). This has recently aroused the attention not only to focus on clinical care but rather to be holistic and client-centered, looking beyond morbidity and mortality. The study assessed the QOL and associated factors among patients with cervical cancer (CC) after the completion of chemoradiotherapy. Methods A cross-sectional analytical study was conducted at Ocean Road Cancer Institute (ORCI) from September to November 2020. A total of 323 CC patients were interviewed with a structured questionnaire of QOL, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and its cervical cancer module (EORTC QLQ-CX24). The QOL domains, socio-demographic and clinical variables were analyzed with Mann–Whitney and Kruskal–Wallis on SPSS version 23, and a P < 0.05 was considered significant. Results More than half (54.8%) of the CC patients had a good overall QOL. Overall, QOL was affected by education (P = 0.019), smoking (0.044), sexual partner (P = 0.000), treatment modality (P = 0.018), and time since completion of treatment (P = 0.021). Patients who underwent external beam radiation suffered from significant side effect symptoms (P < 0.05) while those who underwent combined external beam radiation and brachytherapy had higher functioning in most domains (P < 0.05). Conclusions A significant improvement in QOL was observed after chemoradiotherapy and was affected by socio-demographic and clinical variables. Thus, calls for individualized care in addressing these distressing symptoms.

Although progestin has been used to treat endometrial hyperplasia and endometrial carcinoma (EC), its therapeutic efficacy is limited. In order to improve this, the underlining mechanisms of the effects of progestin need to be elucidated in more detail. In the present study, we examined the involvement of mitogen-inducible gene-6 (MIG6), a negative regulator of the EGF receptor, in the progestin-mediated growth suppression of endometrial epithelia. The immunohistochemical expression of MIG6 was elevated in the early to mid-secretory phases of normal endometrium and also with endometrial hyperplasia after medroxyprogesterone acetate (MPA) therapy. The addition of progesterone (P4) to progesterone receptor (PR)-positive EC cells reduced the viability and induced MIG6 messenger RNA (mRNA) and protein expression. The silencing of MIG6 using siRNA eliminated the P4-mediated reduction of EC cell viability, indicating that MIG6 is an essential downstream component of PR-mediated growth suppression. In order to enhance PR-driven signals, we examined the effects of histone deacetylase (HDAC) inhibitors because histone acetylation has been shown to increase the expression of PR. The addition of three HDAC inhibitors (panobinostat, LBH589; trichostatin A, TSA; suberoylanilide hydroxamic acid, SAHA) decreased the viability of EC cells and up-regulated the expression of PR and MIG6, and these effects were the strongest with LBH589. The addition of LBH589 and MPA synergistically decreased the viability and increased apoptosis in EC cells. These results indicate that LBH589 has potential as an enhancer of progestin therapy via the up-regulation of PR and MIG6.

Objective: Although estrogen has been regarded as a risk factor for endometrial carcinoma, its concentrationdependent carcinogenetic effects remain unclear, because most endometrial carcinomas occur in post-menopausal women, whose serum estrogen levels are relatively low. We previously reported that high levels of estradiol (E2) may suppress endometrial carcinogenesis by up-regulating DNA mismatch repair (MMR) in vitro. The present study was undertaken to further examine the carcinogenetic role of estrogen at various concentrations in vivo.Methods: N-methyl-N-nitrosourea (MNU) was injected into the uterine cavity of 29 mice, and E2 was administered by pellets or orally. Uteri were removed for histological examinations 24 weeks later, and serum E2 levels were measured. The immunohistochemical expression of MMR proteins in uterine epithelia was investigated.Results: Of 29 mice, 8, 8, 8, and 5 showed atrophic, normal, hyperplastic, and carcinomatous endometria, respectively. The mean E2 levels of each group were 0.2 pg/ml, 3.8 pg/ml, 190.0 pg/ml, and 6.7 pg/ml, with significant differences. The expression of the MMR proteins was stronger in mice with elevated E2. Conclusion:Elevated E2 levels preferentially induced endometrial hyperplasia rather than carcinoma, and this may be mediated by MMR proteins. These results indicate that modest E2 is needed, whereas elevated E2 levels are not necessarily advantageous for carcinogenesis, suggesting the importance of low-chronic (un-opposed) estrogen in human endometrial carcinogenesis.